Seven transmembrane-spanning receptors (7TMRs or G protein-coupled receptors, GPCRs) represent the largest family of signal-transducing molecules known. For example, 7TMRs comprise more than 4% of the genes in Caenorhabditis elegans. 7TMRs convey signals for light and many extracellular regulatory molecules, such as, hormones, growth factors and neurotransmitters, that regulate every cell in the body. Dysregulation of 7TMRs has been found in a growing number of human diseases and 7TMRs have been estimated to be the targets of more than 30% of the drugs used in clinical medicine today. Thus, understanding how 7TMRs function is an important goal of biomedical research. We continue to apply molecular modeling approaches to the study of the molecular details of ligand binding to 7TMRs and to the mechanism of activation of these receptors. We study receptors for thyrotropin-releasing hormone (TRH) (TRH-Rs), for thyroid-stimulating hormone (TSH-R) and for free fatty acids (GPR40/FFAR1) as model 7TMRs. During this year, we studied several aspects of binding of low molecular weight (LMW) ligands to TSH-R and used novel molecular models of the TSH-R in an iterative fashion with experiments to better define the TSH-R binding cavity. Based on molecular models, we proposed a mechanism for activation of the two subtypes of TRH-Rs, TRH-R1 and TRH-R2, and developed a new computational approach to distinguish binding and activation of TRH-R1 versus TRH-R2. Lastly, we developed the first model of GPR40 and used it to begin to understand how free fatty acids and LMW organic ligands bind to GPR40.